Methacrylonitrile: in vivo metabolism to cyanide in rats, mice, and gerbils.

Methacrylonitrile (MeAN), a widely used industrial chemical, is metabolized to cyanide in rats, mice, and gerbils. Cyanide levels following oral administration of 0.5 or 1 LD50 dose of MeAN were determined in blood and organs of treated animals. Male Mongolian gerbils were 50-fold more sensitive to MeAN than Sprague-Dawley rats and about 5-fold more sensitive than were Albino-Swiss mice. The signs of MeAN toxicity were typically those of cyanide-related central nervous system poisoning in all the three species. The difference was in the time required for the onset of these signs. Mice and gerbils developed the toxicity signs faster than the rats. All the three species showed a dose-response relationship in metabolism of MeAN to cyanide. However, in mice and gerbils, the peak blood concentration of cyanide occurred 1 hr following MeAN administration, whereas it took 3 hr for rats to reach peak blood cyanide levels. In the rats treated with phenobarbital or those starved for 18 hr, the metabolism of MeAN to cyanide increased significantly (159-178% and 181-201% of control, respectively), and the treatment of rats with CoCl2 resulted in a significant decrease in MeAN metabolism to cyanide (60-68% of control). These studies indicate a distinct species difference in the toxicity and metabolism of MeAN.

Metabolism of methacrylonitrile to cyanide: in vitro studies.

In liver fractions from male Sprague-Dawley rats, the metabolism of methacrylonitrile (MeAN) to cyanide (CN-) was localized in microsomal fraction and required reduced nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen for maximal activity. The biotransformation of MeAN to CN- was characterized with respect to time, microsomal protein concentration, pH, and temperature. Metabolism of MeAN was increased in microsomes obtained from phenobarbital-treated rats (310% of control) and decreased with CoCl2 and SKF 525 A treatments (55% and 61%, respectively). Addition of the epoxide hydratase inhibitor, 1,1,1-trichloropropane 2,3-oxide, decreased the formation of CN- from MeAN. Addition of glutathione, cysteine, D-penicillamine, and 2-mercaptoethanol enhanced the released of CN- from MeAN. These findings indicate that MeAN is metabolized to CN- via a cytochrome P-450-dependent mixed-function oxidase system.